The Disease.
FRDA is an orphan disease that affects approximately 3:100,000 individuals in Caucasian populations. Generally within 10 to 15 years from onset it leads to loss of deambulation and complete disability, with premature death often caused by cardiac insufficiency. Symptoms usually appear late in the first decade or early in the second decade of life, and include gait instability and general clumsiness. Gait ataxia has both cerebellar and sensory features, involves truncus and limbs, and is both progressive and generally unremitting. Swaying is common and, as it becomes more severe, eventually requires constant support and wheelchair use. Dysarthria occurs early in the disease and ultimately leads to complete speech impairment. Furthermore, dysphagia is a late feature and may require artificial feeding. Loss of peripheral neurons in dorsal root ganglia is the preeminent pathological finding. Ventricular hypertrophy characterizes the cardiac picture, and may progressively lead to congestive heart failure and fatal arrhythmias. A significant minority of patients also develop diabetes mellitus via mechanisms that are not yet clearly defined.
FRDA is caused by homozygous hyperexpansion of GAA triplets within the first intron of FXN, a highly conserved five-exon gene located on the long arm of human chromosome 9, coding for the protein frataxin. Pathological GAA expansions (from ˜70 to >1,000 triplets) result in “sticky” DNA structures and epigenetic changes that severely reduce transcription of the FXN gene. FRDA patients live with 10-30% residual frataxin, and the severity of the disease is usually proportional to the number of GAA triplets and the consequent degree of frataxin reduction. A minority of FRDA patients, so-called compound heterozygotes, has pathological GAA expansions on one FXN allele and loss-of-function mutations on the other.
Current Therapeutic Approaches.
There is currently no specific therapy to prevent the progression of the disease. Most therapeutic approaches are aimed at reducing mitochondrial dysfunction and iron overload, and are therefore based on the use of anti-oxidants or iron chelators. While numerous approaches to treating FRDA have been explored, each of those approaches has significant limitations. Thus, a need exists in the art for new methods for more effectively treating FRDA.